EXPERIMENTAL AND CALCULATED RESULTS OF A FLUTTER INVESTIGATION OF SOME VERY LOW ASPECT-RATIO FLAT-PLATE SURFACES AT MACH NUMBERS FROM 0.62 TO 3.00

Flutter investigation of very low aspect-ratio flat-plate surfaces at subsonic and supersonic spee

Investigation of an all-movable control surface at a mach number of 6.86 for possible flutter

Movable tail surface for aircraft control without flutter using X-15 scale model at hypersonic spee

Precision medicine for suicidality: from universality to subtypes and personalization

Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a ‘liquid biopsy’ approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies. Such markers may reflect and/or be a proxy for the core biology of suicide. We were successful in this endeavor, using a comprehensive stepwise approach, leading to a wealth of findings. Steps 1, 2 and 3 were discovery, prioritization and validation for tracking suicidality, resulting in a Top Dozen list of candidate biomarkers comprising the top biomarkers from each step, as well as a larger list of 148 candidate biomarkers that survived Bonferroni correction in the validation step. Step 4 was testing the Top Dozen list and Bonferroni biomarker list for predictive ability for suicidal ideation (SI) and for future hospitalizations for suicidality in independent cohorts, leading to the identification of completely novel predictive biomarkers (such as CLN5 and AK2), as well as reinforcement of ours and others previous findings in the field (such as SLC4A4 and SKA2). Additionally, we examined whether subtypes of suicidality can be identified based on mental state at the time of high SI and identified four potential subtypes: high anxiety, low mood, combined and non-affective (psychotic). Such subtypes may delineate groups of individuals that are more homogenous in terms of suicidality biology and behavior. We also studied a more personalized approach, by psychiatric diagnosis and gender, with a focus on bipolar males, the highest risk group. Such a personalized approach may be more sensitive to gender differences and to the impact of psychiatric co-morbidities and medications. We compared testing the universal biomarkers in everybody versus testing by subtypes versus personalized by gender and diagnosis, and show that the subtype and personalized approaches permit enhanced precision of predictions for different universal biomarkers. In particular, LHFP appears to be a strong predictor for suicidality in males with depression. We also directly examined whether biomarkers discovered using male bipolars only are better predictors in a male bipolar independent cohort than universal biomarkers and show evidence for a possible advantage of personalization. We identified completely novel biomarkers (such as SPTBN1 and C7orf73), and reinforced previously known biomarkers (such as PTEN and SAT1). For diagnostic ability testing purposes, we also examined as predictors phenotypic measures as apps (for suicide risk (CFI-S, Convergent Functional Information for Suicidality) and for anxiety and mood (SASS, Simplified Affective State Scale)) by themselves, as well as in combination with the top biomarkers (the combination being our a priori primary endpoint), to provide context and enhance precision of predictions. We obtained area under the curves of 90% for SI and 77% for future hospitalizations in independent cohorts. Step 5 was to look for mechanistic understanding, starting with examining evidence for the Top Dozen and Bonferroni biomarkers for involvement in other psychiatric and non-psychiatric disorders, as a mechanism for biological predisposition and vulnerability. The biomarkers we identified also provide a window towards understanding the biology of suicide, implicating biological pathways related to neurogenesis, programmed cell death and insulin signaling from the universal biomarkers, as well as mTOR signaling from the male bipolar biomarkers. In particular, HTR2A increase coupled with ARRB1 and GSK3B decreases in expression in suicidality may provide a synergistic mechanistical corrective target, as do SLC4A4 increase coupled with AHCYL1 and AHCYL2 decrease. Step 6 was to move beyond diagnostics and mechanistical risk assessment, towards providing a foundation for personalized therapeutics. Items scored positive in the CFI-S and subtypes identified by SASS in different individuals provide targets for personalized (psycho)therapy. Some individual biomarkers are targets of existing drugs used to treat mood disorders and suicidality (lithium, clozapine and omega-3 fatty acids), providing a means toward pharmacogenomics stratification of patients and monitoring of response to treatment. Such biomarkers merit evaluation in clinical trials. Bioinformatics drug repurposing analyses with the gene expression biosignatures of the Top Dozen and Bonferroni-validated universal biomarkers identified novel potential therapeutics for suicidality, such as ebselen (a lithium mimetic), piracetam (a nootropic), chlorogenic acid (a polyphenol) and metformin (an antidiabetic and possible longevity promoting drug). Finally, based on the totality of our data and of the evidence in the field to date, a convergent functional evidence score prioritizing biomarkers that have all around evidence (track suicidality, predict it, are reflective of biological predisposition and are potential drug targets) brought to the fore APOE and IL6 from among the universal biomarkers, suggesting an inflammatory/accelerated aging component that may be a targetable common denominator

Leibniz, Acosmism, and Incompossibility

Leibniz claims that God acts in the best possible way, and that this includes creating exactly one world. But worlds are aggregates, and aggregates have a low degree of reality or metaphysical perfection, perhaps none at all. This is Leibniz’s tendency toward acosmism, or the view that there this no such thing as creation-as-a-whole. Many interpreters reconcile Leibniz’s acosmist tendency with the high value of worlds by proposing that God sums the value of each substance created, so that the best world is just the world with the most substances. I call this way of determining the value of a world the Additive Theory of Value (ATV), and argue that it leads to the current and insoluble form of the problem of incompossibility. To avoid the problem, I read “possible worlds” in “God chooses the best of all possible worlds” as referring to God’s ideas of worlds. These ideas, though built up from essences, are themselves unities and so well suited to be the value bearers that Leibniz’s theodicy requires. They have their own value, thanks to their unity, and that unity is not preserved when more essences are added

Nonalbuminuric Renal Impairment in Type 2 Diabetic Patients and in the General Population (National Evaluation of the Frequency of Renal Impairment cO-existing with NIDDM [NEFRON] 11)

OBJECTIVE Most diabetic patients with impaired renal function have a urinary albumin excretion rate in the normal range. In these patients, the etiology of renal impairment is unclear, and it is also unclear whether this nonalbumunuric renal impairment is unique to diabetes. RESEARCH DESIGN AND METHODS In this study, we examined the frequency and predictors of nonalbumunuric renal impairment (estimated glomerular filtration rate [eGFR] <60 ml/min per 1.73 m(2)) in a nationally representative cohort of 3,893 patients with type 2 diabetes and compared our findings with rates observed in the general population from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) survey (n = 11,247). RESULTS Of the 23.1% of individuals with type 2 diabetes who had eGFR <60 ml/min per 1.73 m(2) (95% CI 21.8-24.5%), more than half (55%) had a urinary albumin excretion rate that was persistently in the normal range. This rate of renal impairment was predictably higher than that observed in the general population (adjusted odds ratio 1.3, 95% CI 1.1-1.5, P < 0.01) but was solely due to chronic kidney disease associated with albuminuria. In contrast, renal impairment in the absence of albuminuria was less common in those with diabetes than in the general population, independent of sex, ethnicity, and duration of diabetes (0.6, 0.5-0.7, P < 0.001). CONCLUSIONS Nonalbuminuric renal impairment is not more common in those with diabetes. However, its impact may be more significant. New studies are required to address the pathogenesis, prevention, and treatment of nonalbuminuric renal disease

A fruit diet rather than invertebrate diet maintains a robust innate immunity in an omnivorous tropical songbird

Experiments were funded by the Royal Netherlands Academy of Arts and Sciences (KNAW) Academy Ecology Fund to C.J.N—(KENMERK J1618/ECO/G437). C.J.N. was supported by a studentship funded by the Leventis Conservation Foundation through the University of St. Andrews UK and an Ubbo Emmius grant of the University of Groningen, The Netherlands. B.I.T. was supported by the Netherlands Organisation for Scientific Research (NWO‐Vidi 864.10.012).1. Diet alteration may lead to nutrient limitations even in the absence of food limitation, and this may affect physiological functions, including immunity. Nutrient limitations may also affect the maintenance of body mass and key life history events that may affect immune function. Yet, variation in immune function is largely attributed to energetic trade-offs rather than specific nutrient constraints. 2. To test the effect of diet on life history traits, we tested how diet composition affects innate immune function, body mass and moult separately and in combination with each other, and then used path analyses to generate hypotheses about the mechanistic connections between immunity and body mass under different diet composition. 3. We performed a balanced parallel and crossover design experiment with omnivorous common bulbuls Pycnonotus barbatus in out-door aviaries in Nigeria. We fed 40 wild-caught bulbuls ad libitum on fruits or invertebrates for 24 weeks, switching half of each group between treatments after 12 weeks. We assessed innate immune indices (haptoglobin, nitric oxide and ovotransferrin concentrations, and haemagglutination and haemolysis titres), body mass and primary moult, fortnightly. We simplified immune indices into three principal components (PCs), but we explored mechanistic connections between diet, body mass and each immune index separately. 4. Fruit fed bulbuls had higher body mass, earlier moult and showed higher values for two of the three immune PCs compared to invertebrate fed bulbuls. These effects were reversed when we switched bulbuls between treatments after 12 weeks. Exploring the correlations between immune function, body mass and moult, showed that an increase in immune function was associated with a decrease in body mass and delayed moult in invertebrate fed bulbuls, while fruit fed bulbuls maintained body mass despite variation in immune function. Path analyses indicated that diet composition was most likely to affect body mass and immune indices directly and independently from each other. Only haptoglobin concentration was indirectly linked to diet composition via body mass. 5. We demonstrated a causal effect of diet composition on innate immune function, body mass and moult: bulbuls were in better condition when fed on fruits than invertebrates, confirming that innate immunity is nutrient specific. Our results are unique because they show a reversible effect of diet composition on wild adult birds whose immune systems are presumably fully developed and adapted to wild conditions – demonstrating a short-term consequence of diet alteration on life history traits.Publisher PDFPeer reviewe

Association of APOE polymorphism with chronic kidney disease in a nationally representative sample: a Third National Health and Nutrition Examination Survey (NHANES III) Genetic Study

<p>Abstract</p> <p>Background</p> <p>Apolipoprotein E polymorphisms (<it>APOE</it>) have been associated with lowered glomerular filtration rate (GFR) and chronic kidney disease (CKD) with e2 allele conferring risk and e4 providing protection. However, few data are available in non-European ethnic groups or in a population-based cohort.</p> <p>Methods</p> <p>The authors analyzed 5,583 individuals from the Third National Health and Nutrition Examination Survey (NHANES III) to determine association with estimated GFR by the Modification of Diet in Renal Disease (MDRD) equation and low-GFR cases. Low-GFR cases were defined as GFR <75 ml/min/1.73 m²; additionally, GFR was analyzed continuously.</p> <p>Results</p> <p>In univariate analysis, the e4 allele was negatively associated with low-GFR cases in non-Hispanic whites, odds ratio (OR): 0.76, 95% confidence interval (CI): 0.60, 0.97. In whites, there was a significant association between increasing <it>APOE </it>score (indicating greater number of e2 alleles) and higher prevalence of low-GFR cases (OR: 1.21, 95%CI: 1.01, 1.45). Analysis of continuous GFR in whites found the e4 allele was associated with higher levels of continuous GFR (β-coefficient: 2.57 ml/min/1.73 m², 95%CI: 0.005, 5.14); in non-Hispanic blacks the e2 allele was associated with lower levels of continuous GFR (β-coefficient: -3.73 ml/min/1.73 m², 95%CI: -6.61, -0.84). <it>APOE </it>e2 and e4 alleles were rare and not associated with low-GFR cases or continuous GFR in Mexican Americans.</p> <p>Conclusion</p> <p>In conclusion, the authors observed a weak association between the <it>APOE </it>e4 allele and low-GFR cases and continuous GFR in non-Hispanic whites, and the <it>APOE </it>e2 allele and continuous GFR in non-Hispanic blacks, but found no association with either measure of kidney function in Mexican Americans. Larger studies including multiethnic groups are needed to determine the significance of this association.</p

Soluble tumor necrosis factor receptor 1 and 2 predict outcomes in advanced chronic kidney disease : a prospective cohort study

Background : Soluble tumor necrosis factor receptors 1 (sTNFR1) and 2 (sTNFR2) have been associated to progression of renal failure, end stage renal disease and mortality in early stages of chronic kidney disease (CKD), mostly in the context of diabetic nephropathy. The predictive value of these markers in advanced stages of CKD irrespective of the specific causes of kidney disease has not yet been defined. In this study, the relationship between sTNFR1 and sTNFR2 and the risk for adverse cardiovascular events (CVE) and all-cause mortality was investigated in a population with CKD stage 4-5, not yet on dialysis, to minimize the confounding by renal function. Patients and methods : In 131 patients, CKD stage 4-5, sTNFR1, sTNFR2 were analysed for their association to a composite endpoint of all-cause mortality or first non-fatal CVE by univariate and multivariate Cox proportional hazards models. In the multivariate models, age, gender, CRP, eGFR and significant comorbidities were included as covariates. Results : During a median follow-up of 33 months, 40 events (30.5%) occurred of which 29 deaths (22.1%) and 11 (8.4%) first non-fatal CVE. In univariate analysis, the hazard ratios (HR) of sTNFR1 and sTNFR2 for negative outcome were 1.49 (95% confidence interval (CI): 1.28-1.75) and 1.13 (95% CI: 1.06-1.20) respectively. After adjustment for clinical covariables (age, CRP, diabetes and a history of cardiovascular disease) both sTNFRs remained independently associated to outcomes (HR: sTNFR1: 1.51, 95% CI: 1.30-1.77; sTNFR2: 1.13, 95% CI: 1.06-1.20). A subanalysis of the non-diabetic patients in the study population confirmed these findings, especially for sTNFR1. Conclusion : sTNFR1 and sTNFR2 are independently associated to all-cause mortality or an increased risk for cardiovascular events in advanced CKD irrespective of the cause of kidney disease